δ-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it

ABSTRACT

A δ-crystalline form of ivabradine hydrochloride of formula (I): 
                         
characterised by its powder X-ray diffraction data.
 
     Medicinal products containing the same which are useful as bradycardics.

The present invention relates to the δ-crystalline form of ivabradine hydrochloride of formula (I)

to a process for its preparation and to pharmaceutical compositions containing it.

Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP 0 534 859.

In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light or oxygen level.

The patent specification EP 0 534 859 describes a synthesis process for ivabradine and its hydrochloride. However, that document does not specify the conditions for obtaining ivabradine in a form that exhibits those characteristics in a reproducible manner.

The Applicant has now found that a particular salt of ivabradine, the hydrochloride, can be obtained in a well defined crystalline form that exhibits valuable characteristics for stability and processability.

More specifically, the present invention relates to the δ-crystalline form of ivabradine hydrochloride, characterised by the following powder X-ray diffraction diagram, measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees), line height (expressed in counts), line area (expressed in counts x degrees), line width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å):

Angle 2 Area Line theta Height (counts × FWHM Interplanar no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.1 1115 110 0.1004 21.753 2 6.8 183 145 0.8029 12.907 3 8.4 755 75 0.1004 10.531 4 10.9 1104 128 0.1171 8.087 5 12.2 195 19 0.1004 7.268 6 14.3 569 75 0.1338 6.214 7 14.7 1847 274 0.1506 6.013 8 15.3 1734 315 0.184 5.802 9 16.3 1164 154 0.1338 5.442 10 16.8 3420 734 0.2175 5.269 11 17.5 790 78 0.1004 5.069 12 17.9 3389 503 0.1506 4.960 13 19.2 2467 407 0.1673 4.635 14 19.8 145 29 0.2007 4.477 15 20.4 313 52 0.1673 4.362 16 21.2 928 169 0.184 4.198 17 21.7 2093 414 0.2007 4.099 18 22.2 3850 635 0.1673 4.007 19 22.5 576 76 0.1338 3.948 20 23.1 1588 236 0.1506 3.855 21 24.8 1665 247 0.1506 3.594 22 25.2 1212 120 0.1004 3.534 23 25.6 1507 249 0.1673 3.477 24 26.7 2042 303 0.1506 3.342 25 27.6 2281 414 0.184 3.229 26 28.4 485 96 0.2007 3.138 27 29.6 599 99 0.1673 3.014

The invention relates also to a process for the preparation of the δ-crystalline form of ivabradine hydrochloride, which process is characterised in that acetonitrile or a mixture of acetonitrile and water is preheated, ivabradine hydrochloride is added, the solution obtained is allowed to cool at room temperature, held at room temperature until crystallisation is complete, and the crystals formed are collected.

-   -   In the crystallisation process according to the invention it is         possible to use ivabradine hydrochloride obtained by any         process, for example ivabradine hydrochloride obtained by the         preparation process described in patent specification EP 0 534         859.     -   The solution may advantageously be seeded during the cooling         step.     -   The acetonitrile or mixture of acetonitrile and water is         preferably preheated to a temperature between 60° C. and reflux,         more preferably between 65 and 75° C.     -   The dilution is preferably more than 15 ml/g, more preferably         between 50 and 100 ml/g.

The invention relates also to pharmaceutical compositions comprising as active ingredient the δ-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert and non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations and drinkable suspensions.

The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. The dosage varies from 1 to 500 mg per day in one or more administrations.

The Examples that follow illustrate the invention.

The X-ray powder diffraction spectrum was measured under the following experimental conditions:

-   -   PANalytical X'Pert Pro diffractometer, X'Celerator detector,         temperature-regulated chamber,     -   voltage 45 kV, intensity 40 mA,     -   mounting θ-θ,     -   nickel (Kβ) filter,     -   incident-beam and diffracted-beam Soller slit: 0.04 rad,     -   automatic divergence slits : irradiated length of 10 mm,     -   mask: 10 mm,     -   antiscatter slit: ½°,     -   measurement mode: continuous from 3° to 30°, in increments of         0.017°,     -   measurement time per step : 19.7 s,     -   total time: 4 min 32 s,     -   measurement speed : 0.108°/s,     -   measurement temperature: ambient.

EXAMPLE 1 δ-crystalline Form of Ivabradine Hydrochloride

160 ml of acetonitrile are preheated to 70° C. and then 2 g of ivabradine hydrochloride obtained according to the process described in patent specification EP 0 534 859 are added, in portions, with stirring until dissolution is complete. The solution is then stored at ambient temperature for 2 days. The crystals are removed by filtration in vacuo and are spread out onto a crystallisation plate.

The water content of the product obtained, determined by coulometry, is 2.8%.

Powder X-ray diffraction diagram:

The powder X-ray diffraction profile (diffraction angles) of the δ-form of ivabradine hydrochloride is given by the significant lines collated in the following table:

Angle 2 Area Line theta Height (counts × FWHM Interplanar no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.1 1115 110 0.1004 21.753 2 6.8 183 145 0.8029 12.907 3 8.4 755 75 0.1004 10.531 4 10.9 1104 128 0.1171 8.087 5 12.2 195 19 0.1004 7.268 6 14.3 569 75 0.1338 6.214 7 14.7 1847 274 0.1506 6.013 8 15.3 1734 315 0.184 5.802 9 16.3 1164 154 0.1338 5.442 10 16.8 3420 734 0.2175 5.269 11 17.5 790 78 0.1004 5.069 12 17.9 3389 503 0.1506 4.960 13 19.2 2467 407 0.1673 4.635 14 19.8 145 29 0.2007 4.477 15 20.4 313 52 0.1673 4.362 16 21.2 928 169 0.184 4.198 17 21.7 2093 414 0.2007 4.099 18 22.2 3850 635 0.1673 4.007 19 22.5 576 76 0.1338 3.948 20 23.1 1588 236 0.1506 3.855 21 24.8 1665 247 0.1506 3.594 22 25.2 1212 120 0.1004 3.534 23 25.6 1507 249 0.1673 3.477 24 26.7 2042 303 0.1506 3.342 25 27.6 2281 414 0.184 3.229 26 28.4 485 96 0.2007 3.138 27 29.6 599 99 0.1673 3.014

EXAMPLE 2 Pharmaceutical Composition

Formula for the preparation of 1000 tablets each containing 5 mg of ivabradine base:

Compound of Example 1 5.39 g Maize starch 20 g Anhydrous colloidal silica 0.2 g Mannitol 63.91 g PVP 10 g Magnesium stearate 0.5 g 

1. A δ-crystalline form of ivabradine hydrochloride of formula (I):

exhibiting essentially the following powder X-ray diffraction data, measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees), line height (expressed in counts), line area (expressed in counts × degrees), line width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å): Angle 2 Area Line theta Height (counts × FWHM Interplanar no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.1 1115 110 0.1004 21.753 2 6.8 183 145 0.8029 12.907 3 8.4 755 75 0.1004 10.531 4 10.9 1104 128 0.1171 8.087 5 12.2 195 19 0.1004 7.268 6 14.3 569 75 0.1338 6.214 7 14.7 1847 274 0.1506 6.013 8 15.3 1734 315 0.184 5.802 9 16.3 1164 154 0.1338 5.442 10 16.8 3420 734 0.2175 5.269 11 17.5 790 78 0.1004 5.069 12 17.9 3389 503 0.1506 4.960 13 19.2 2467 407 0.1673 4.635 14 19.8 145 29 0.2007 4.477 15 20.4 313 52 0.1673 4.362 16 21.2 928 169 0.184 4.198 17 21.7 2093 414 0.2007 4.099 18 22.2 3850 635 0.1673 4.007 19 22.5 576 76 0.1338 3.948 20 23.1 1588 236 0.1506 3.855 21 24.8 1665 247 0.1506 3.594 22 25.2 1212 120 0.1004 3.534 23 25.6 1507 249 0.1673 3.477 24 26.7 2042 303 0.1506 3.342 25 27.6 2281 414 0.184 3.229 26 28.4 485 96 0.2007 3.138 27 29.6 599 99 0.1673  3.014.


2. A process for the preparation of the δ-crystalline form of ivabradine hydrochloride of claim 1, wherein acetonitrile or a mixture of acetonitrile and water is preheated, ivabradine hydrochloride is added, the solution obtained is allowed to cool at room temperature, held at room temperature until crystallization is complete, and the crystals formed are collected.
 3. The process of claim 2, wherein the solution of ivabradine hydrochloride is seeded during the cooling step.
 4. A solid pharmaceutical composition comprising as active ingredient the δ-crystalline form of ivabradine hydrochloride of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.
 5. A method for treating a condition selected from angina pectoris, myocardial infarct and heart failure, such method comprising the step of administering to a living animal body, including a human, a therapeutically effective amount of δ-crystalline form of ivabradine hydrochloride of claim
 1. 